Modified Vaccinia Ankara (MVA) virus is related to vaccinia virus, a member of the genera Orthopoxvirus, in the family of Poxviridae. MVA was generated by 516 serial passages on chicken embryo fibroblasts of the Ankara strain of vaccinia virus (CVA) (for review see Mayr, A., et al. Infection 3:6-14 (1975)). As a consequence of these long-term passages, the genome of the resulting MVA virus had about 31 kilobases of its genomic sequence deleted and, therefore, was described as highly host cell restricted for replication to avian cells (Meyer, H. et al., J. Gen. Virol. 72:1031-1038 (1991)). It was shown in a variety of animal models that the resulting MVA was significantly avirulent (Mayr, A. & Danner, K., Dev. Biol. Stand. 41:225-34 (1978)). Additionally, this MVA strain has been tested in clinical trials as a vaccine to immunize against the human smallpox disease (Mayr et al., Zbl. Bakt. Hyg. I, Abt. Org. B 167:375-390 (1987); Stickl et al., Dtsch. med. Wschr. 99:2386-2392 (1974)). These studies involved over 120,000 humans, including high-risk patients, and proved that, compared to vaccinia-based vaccines, MVA had diminished virulence or infectiousness, while it induced a good specific immune response. In the following decades, MVA was engineered for use as a viral vector for recombinant gene expression or as a recombinant vaccine (Sutter, G. et al., Vaccine 12:1032-40 (1994)).
Even though Mayr et al. demonstrated during the 1970s that MVA is highly attenuated and avirulent in humans and mammals, certain investigators have reported that MVA is not fully attenuated in mammalian and human cell lines since residual replication might occur in these cells. (Blanchard et al., J Gen Virol 79:1159-1167 (1998); Carroll & Moss, Virology 238:198-211 (1997); Altenberger, U.S. Pat. No. 5,185,146; Ambrosini et al., J Neurosci Res 55(5):569 (1999)). It is assumed that the results reported in these publications have been obtained with various known strains of MVA, since the viruses used essentially differ in their properties, particularly in their growth behavior in various cell lines. Such residual replication is undesirable for various reasons, including safety concerns in connection with use in humans.
Strains of MVA having enhanced safety profiles for the development of safer products, such as vaccines or pharmaceuticals, have been described. See U.S. Pat. Nos. 6,761,893 and 6,193,752. Such strains are capable of reproductive replication in non-human cells and cell lines, especially in chicken embryo fibroblasts (CEF), but are not capable of reproductive replication in certain human cell lines known to permit replication with known vaccinia strains. Those cell lines include a human keratinocyte cell line, HaCat (Boukamp et al. J Cell Biol 106(3):761-71 (1988)), a human cervix adenocarcinoma cell line, HeLa (ATCC No. CCL-2), a human embryo kidney cell line, 293 (ECACC No. 85120602), and a human bone osteosarcoma cell line, 143B (ECACC No. 91112502). Such viral strains are also not capable of reproductive replication in vivo, for example, in certain mouse strains, such as the transgenic mouse model AGR 129, which is severely immune-compromised and highly susceptible to a replicating virus. See U.S. Pat. No. 6,761,893. One such MVA strain and its derivatives and recombinants, referred to as “MVA-BN®,” have been described. See U.S. Pat. Nos. 6,761,893 and 6,193,752.
MVA and MVA-BN® have each been engineered for use as a viral vector for recombinant gene expression or as a recombinant vaccine. See, e.g., Sutter, G. et al., Vaccine 12:1032-40 (1994), U.S. Pat. Nos. 6,761,893 and 6,193,752.
Cancer-related diseases are a leading cause of mortality and morbidity worldwide. For example, in the US alone, it is estimated that one in six men will suffer from prostate cancer. Moreover, autopsy studies show that a significant proportion of the male population is known to carry the disease, albeit at its earliest non-malignant stages, as early as by the age of 30. See, e.g., Taichman et al., JCI 117(9):2351-2361 (2007); Webster et al., J. Clin. Oncol. 23:8262-8269 (2005). Recent approaches to cancer immunotherapy have included vaccination with tumor-associated antigens. In certain instances, such approaches have included use of a delivery system to promote host immune responses to tumor-associated antigens. Such delivery systems have included recombinant viral vectors, as well as cell-based therapies. See, e.g., Harrop et al., Front. Biosci. 11:804-817 (2006); Arlen et al., Semin. Oncol. 32:549-555 (2005); Liu et al., Proc. Natl. Acad. Sci. USA 101 (suppl. 2):14567-14571 (2004). MVA has been used as a vaccine vehicle for the 5T4 oncofetal antigen in clinical trials in metastatic colorectal, metastatic renal and hormone-refractory prostate cancer patients. Amato, R J., Expert Opin. Biol. Ther. 7(9): 1463-1469 (2007).
Among the known tumor-associated antigens are prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP). See, e.g., Taichman et al., JCI 117(9): 2351-2361 (2007); Webster et al., J. Clin. Oncol. 23:8262-8269 (2005). PSA is produced by the prostate and is found in an increased amount in the blood of men who have prostate cancer, benign prostatic hyperplasia, or infection or inflammation of the prostate. PSA has been identified as a target for cell-mediated immunotherapy approaches to cancer treatment. See, e.g., McNeel, D. G., Curr. Opin. Urol. 17:175-181 (2007); Nelson W. G., Curr. Opin. Urol. 17:157-167 (2007). PAP is an enzyme measured in the blood whose levels may be elevated in patients with prostate cancer which has invaded or metastasized elsewhere. PAP is not elevated unless the tumor has spread outside the anatomic prostatic capsule, either through localized invasion or distant metastasis. Therefore this prostate tumor antigen is being investigated as a target antigen in several human vaccine trials, some with evidence of clinical benefit. See, e.g., McNeel, D. G., Curr. Opin. Urol. 17:175-181 (2007); Waeckerle-Men et al., Cancer Immunol. Immunother. 66:811-821 (2006); Machlenkin et al. Cancer Immunol Immunother. 56(2):217-226 (2007).
PAP containing vaccines have been generated using recombinant vaccinia virus, purified PAP, DNA vaccines, and antigen-loaded dendritic cells. Valone et al., The Cancer Journal 7: Suppl 2:S53-61 (2001); Fong et al., J Immunol. 2001 Dec. 15;167(12):7150-6; Fong et al., J. Immunol. 159(7):3113-7 (1997); Johnson et al., Vaccine 24(3):293-303 (2006); Johnson et al., Cancer Immunol Immunother. 56(6):885-95 (2007). In one study, no antibodies to PAP were detected when dendritic cells pulsed with PAP-GM-CSF were injected into rats. (Valone et al. at S55.). In another study, administration of recombinant vaccinia virus containing genes encoding rat PAP or human PAP did not generate a measurable antibody response to rat or human PAP. (Fong et al. (1997) at 3116-7.) In another study, PAP-specific IgG could be detected in the sera of animals immunized with hPAP protein as well as in animals that received vaccinia virus encoding human PAP vaccination followed by hPAP protein as a booster immunization, but not in animals immunized twice with vaccinia virus encoding human PAP. (Johnson et al. (2007) at 890.)
Active cancer immunotherapy relies on the induction of an immune response against tumor cells in cancer patients. The induction of both humoral and cellular components of adaptive immunity against a broad range of tumor-associated antigens (TAA) and the concomitant activation of components of innate immunity are essential for maximal efficacy of an active immunotherapy product. Specifically, Type 1 or Th1 adaptive immunity characterized by the induction of antigen-specific IFNγ-producing cytotoxic T-cells (CD8 T-cells) is believed to be important for anti-cancer immunotherapy.
Despite the recent advances in cancer treatment, prostate cancer remains the second leading cause of death among American cancer patients. Thus, therapeutic approaches that might better alleviate the disease by targeting multiple aspects of tumor growth and metastasis are needed.
Taxanes, such as paclitaxel and docetaxel, have been used as chemotherapies for cancer patients. See, e.g., Tannock et al., N. Engl. J. Med. 351:1502-1512 (2004). Chemotherapy with taxanes has been combined with different tumor vaccine treatments, resulting in a variety of results. See, Chu et al., J. Immunotherapy 29:367-380 (2006); Machiels et al., Cancer Res. 61:3689-3697 (2001); Prell et al., Cancer Immunol. Immunother. 55:1285-1293 (2006); Arlen et al., Clinical Breast Cancer 7:176-179 (2006); and Arlen et al., Clinical Cancer Res. 12:1260-1269 (2006). The combination of cancer vaccines with chemotherapies has been reviewed in Chong et al., Expert Opin. Phamacother. 6:1-8 (2005); Emens et al., Endocrine-Related Cancer 12:1-17 (2005); and McNeel, D. G., Curr. Opin. Urol. 17:175-181 (2007).
Based on the above, a need in the art exists for reagents and methods for cancer therapy.